3-aminomethylene androstanes



United States Patent 3,128,269 3-AMINOMETHYLENE ANDRQfsTANES Albert Bowers and John Edwards, Mexico City, Mexico, and John Zderic, Palo Alto, Calif., assignors, by mesne assignments, to Syntex Corporation, a corporation of Panama No Drawing. Filed Aug. 1, 1961, Ser. No. 128,363

17 Claims. (Cl. 260239.5)

following formula:

i o R \NHC.

In the above formula, R represents hydrogen or a hydrocarbon carboxylic acyl group containing less than 12 carbon atoms; R may be hydrogen or an alkyl, alkenyl or alkynyl group of up to 8 carbon atoms; R and -R represent hydrogen, lower alkyl, di(lower alkyl) amino lower alkyl, or an aryl or aralkyl group containing up to 8 carbon atoms; and R and R together with the nitrogen atom form a heterocycle as for example piperidine, morph-oline or pyrrolidine.

The acyl group is derived from hydrocarbon carboxylic acids containing less than 12 carbon atoms which may be saturated or unsaturated, of straight, branched, cyclic or cyclic-aliphatic chain, aromatic and may be substituted by functional groups such as hydroxy, alkoxy containing up to carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino, or halogen. Typical ester groups are the acetate, propionate, enanthate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetate, cycl-opentylpropionate, aminoacetate and fi-chloropropion-ate.

The compounds of the present invention are prepared by the process illustrated by the following equation:

O i R II a 3,128,269 Patented Apr. 7, 196,4

ice

In the above formulas, R, R R and R have the same meaning as previously set forth.

In practicing the process above outlined, the starting 3-hydroxymethylene-androstant-17B o1 2-one derivative (I) obtained by reacting A -androstene-l7B-0l-3-one with a N-haloamide, oxidizing the thus formed halohydrin, dehalogenating to form the corresponding 2-keto-17B-hydroxy-androstan which, alternatively, is reacted with ethyl formate to afford the 2-keto-3-hydroxymethylene-androstane-l7B-ol derivative or is first protected at 02 by formation of la ketal, oxidized to form the 17-keto moiety which is then conventionally transformed into the 17maliphatic hydrocarbon-UB-hydroxy grouping, and further reacted with ethyl formate to introduce the 3-hydroxymethylene group as described in the copending US. patent application Serial No. 128,362 filed of even date, is treated with ammonia or an amine such as a di(lovver alkyl)amine, for instance, diethylam-ine in a suitable solvent, for example :dioxane, for a period of time of the order of 72 hours to give the corresponding 3-aminomethylene derivative (H).

When the amine used has a higher boiling point, as for example, piperidine, N-methyl aniline or diethylaiminoethylamine, the starting compound (I) is refluxed with the respective amine in a suitable solvent such as dioxane for a period of time of the order of 24 hours to give the corresponding 3-aminomethylene derivative (II).

The following specific Examples serve to illustrate but are not intended to limit the scope of the present invention:

Example I A solution of 1 g. of 3-hydroxymethylene-androstanl7B-ol-2-one in 75 cc. of dioxane was saturated with ammonia and the reaction mixture kept for 72 hours at room temperature. Water was then added and the resulting precipitate filtered off, washed with water and dried. Recrystallization from methanol-benzene alforded 3-aminomethylene-androstan-17,6-01-2-0ne.

Following the above procedure there were treated 3- hydroxymethylene-17u-methyl-androstan-17B-ol-2-one, 3- hydroxymethylene-17a-vinyl-androstan-l7e-ol-2-one, and 3 hydroxymethylene-l7a-ethiny l-androstan-17,8-01-2-one, affording respectively 3-aminornethylene-17a-rnethyl-androstan-l7fi-ol-2-one, 3-aminomethylene 17cc vinyl-androstan-17-fi-ol-2-one, and 3-aminomethylene-l7a-ethinylandrostan-l7fl-ol-one.

Example II The compounds 3-hydroxymethylene-17ot-methyl-androstan-17,8-oi-2-one-17-acetate, 3-hydroirymethylene-l7avinyl-androstan-l7/3-ol-2-one-17-acetate, and 3-hydroxymethylene-17a-ethinyl-androstan 17fi-ol-2-one-17-acetate are treated in the same manner as described in Example I, thus furnishing correspondingly 3-aminomethylenel7amethyl-andnostan 17/3 ol-2-one-l7-acetate, 3 aminomethylene 17a-vinyl-androstan-17,8-ol-2-one-17-acetate, and 3-aminomethylene 17o; ethynyl-androstan-l7,6-01-2- one-17-acetate.

Example III Following the procedure described in Example I except that ammonia was substituted by diethylamine, there were treated 3-hydroxymethylene-androstan-17,8-ol-2-one, 3-hydroxymethylene-17u-methyl-androstan-17e-ol-2-one, 3-hydroxymethylene-l7a-vinyl-androstan-17/3-ol-2-0ne, 3 hydroxymethylene-lMethinyl-androstan-17,6-ol-2-one, giving respectively 3-N,N,-diethylaminornethylene-androstan- 17fi-ol-2-one, 3-N,N-diethylaminomethylene-l7a-methylandrostan-17e-ol-2-one, 3 -N,N-diethyl-aminomethylene- 17a-vinyl-androstan-17,8-01-2-0ne, and 3 N,N-diethylaminometh-ylene-17u-ethinyl-androstan-17,8-ol-2-one.

Example IV When applying the method of Example III to 3-hydroxymethylene-lh-methyl androstan-175-ol-2-one-17- propionate, 3-hydroxymethylene-17a-vinyl-androstan-17flol-2-one-17-propionate, and S-hydroxymethylene 170cethinyl-androstand7fi-ol-2-one-17-propionate, there were correspondingly obtained 3-N,N-diethylaminornethylene- 17a-methyl-androstan-17fi-ol-2-one-17-propionate, 3-N,N- diethylaminomethylene 17ol-vinyl-androstan-17p-ol-2-one 17-propionate, and 3-N,N-diethylarninomethylene-l7aethinyl-androstan-17fi-ol-2-one-17-propionate.

Example V 1 g. of 3-hydroxymethylene-androstan-17fl-ol-2-one in 30 cc. of dioxane was refluxed with 2 g. of piperidine for 24 hours. The greater part of the solvents was removed by evaporation under reduced pressure. Water was then added, the formed precipitate was filtered ofi, washed and dried. Recrystallization from aeetone-hexane afforded 3- liperidino-methylene-androstan-17B-ol-2-one.

Following exactly the same procedure, there were treated 3-hydroxymethylene-17a-methyl-androstan-17,8-ol- 2-one, 3-hydroxymethylene-17oc-vinyl-androstan-175-01-2- one, and 3-hydroxymethylene-l7a-ethinyl-androstan-175- ol-2-one, affording correspondingly 3-piperidino-methyleue 17oz methyl-androstan-l7fi-ol-2-one, 3-piperidir1omethylene-17u-vinyl-androstan-l7/3-ol-2-0ne, and 3-piperidine-methylene-17ot-ethinyl-androstan-17B-ol-2-one.

Example VI Using the same conditions described in Example V, except that piperidine was substituted by morpholine, there were treated 3-hydroxymethylene-androstan-l7fi-ol-2-one, 3-hydroxymethylene-17 x-methyl androstan-17p-ol-2-one- 17-caproate, 3 hydroxymethylene-17a-vinyl-androstan- 175-ol-2-one-17-caproate, and 3-hydroxymethylene-17aethinyl-androstan-17,8-01-2-one-17 -caproate, affording correspondingly 3-morpholinc-methylene-androstan-175-01-2- one, 3-morpholino-methylene-17a-methyl-androstan-17fiol-2-one-17-caproate, 3-morpholino-methylene-l7a-vinylandrostan-17fiol-2-one-17-caproate, and 3-morpholin0- methylene-17a-ethinyl-androstan-17,B'ol-2-one-17 caproate.

Example VII Following the technique described in Example V except that piperidine was substituted by pyrrolidine, there were treated 3-hydroxymethylene-androstan-17fi-ol-2-one, 3-hydroxymethylene 17a methyl-androstan-17B-0l-2-one-17- cyclopentylpropionate, 3-hydroxymethylene-17a-vinyl-androstan-l7(3-ol-2-one-l7-cyclopentylpropionate, and 3-hydroxymethylene 17oz ethinyl-androstan-17fl-ol-2-one-17- cyclopentylpropionate, affording correspondingly 3-pyrrolidino-methylene-androstan-17p-ol-2-one, 3 pyrrolidinomethylene-17ot-methyl-androstan-17B-0l-2-one-17 cyclopentylpropionate, 3 pyrrolidino-methylenel7ot-vinyl-an drostan-17,8-ol-2-one-l7-cyclopentylpropionate, and 3-pyrrolidinomethylene 17cc ethynyl-androstan-17,8-01-2-0ne- 17-cyclopentylpropionate.

Example VIII In accordance with Example V, except that piperidine was substituted by N-methyl aniline, there were treated 3- hydroxymethylene-androstan17fi-ol-2-one, 3 hydroxymethylene-17ot-methylandrostan-17fl-ol-2-one, 3-hydroxy methylene-17a-vinyl-androstan-l7f3-ol-2-one, and 3-hydroxymethylene-17a-ethinyl-androstan-175-01-2 one atfording correspondingly 3-N-methyl-N-phenylaminomethylene-androstan-17B-ol-2-one, 3-N-methyl-N-phenylaminomethylene-l7a-methyl-androstan-17B-ol-2-one, 3-N-rnethyl-N-phenyl-aminomethylene 17 a-vinyl-androstan- 17 [3-01- 2-one, and 3-N-methyl-N-phenyl-aminomethylene-17methinylandrostan-l7fi-ol-2-one.

4 Example IX Following the procedure described in Example V, but substituting piperidine by diethylaminoethylamine, there were treated 3-hydroxymethylene-androstan-l7,6-ol-2-one, 3-hydroxymethylene-17a-methyl-androstan-175-01-2 one, 3-hydroxymethylene-l7oc-vinyl-androstan l7fi-ol-2-one, 3- hydroxymethylene-l7a-ethinyl-androstan-17B-ol-2-one, af fording respectively 3-N-(N',N'-diethylaminoethyl)-arninomethylene-androstan-17B-ol-2-one, 3-N-(N',N-diethylaminoethyl)-amin0methylene-l7a-methyl androstan-17fiol-2-one, 3 N-(N,N-diethylaminoethyl)-aminomethylene-17m-vinyl-androstan-l7p-ol-2-one, and 3-N-(N',N-diethylamino ethyl) aminomethylene 17a ethinyl androstan-17fi-ol-2-one.

We claim:

1. A compound of the following formula:

wherein R is selected from the :group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; R is a member of the group consisting of hydrogen, an alkyl group, an alkenyl group and an alkynyl group each containing up to 8 carbon atoms; R and R are selected from the group consisting of hydrogen, lower alkyl, di(lower alkyl)amino lower alkyl, an aryl group and an aralkyl group each containing up to 8 carbon atoms; and R and R together with the nitrogen atom form a heterocyclic radical selected from the group consisting of piperidino, morpholino and pyrrolidino.

2. 3aminomethylene-androstan-17,8-ol-2-one.

3. 3 -aminomethylene-17a-methyl-androstan 17 B 01-2- one-17-acetate.

4. 3-aminomethylene-l7a-vinyl-androstan-17,8-01-2-one- 17-acetate.

5. 3 aminomethylene-17a-ethinyl-androstan-175-01-2- one-17-acetate.

6. 3-N,N-diethylaminomethylene androstan 17fl-ol-2 one.

7. 3-N,N-diethylaminomethylene-17ol-methyl-androstan- 17fi-ol-2-one-l7-propionate.

8. 3piperidino-methylene-androstan-175-ol-2-one.

9. 3-piperidinomethylene-l7u-vinyl-androstan-175-01-2- one.

10. 3-morpholino-methylene-androstan-17fl-o1-2-one.

ll. Z-morpholino-methylene-l7a-ethinyl-androstan-l7fiol-2-one-17-caproate.

12. 3-pyrrolidino-methylene-androstan-l7fi-ol-2-one.

13. 3-pyrr0lidino-methylene-17a-methyl-androstan-175- ol-2-0ne-17-cyclopentylpropionate.

14. 3-N-methyl-N-phenyl-aminomethylene androstan- 17/3-ol-2-0ne.

15. 3-N-methyl-N-phenyl aminomethylene-17t-vinylandrostan-17/8-ol-2-one.

16. 3-N-(N,N-diethylaminoethyl)-aminomethylene-androstan-17/3-ol-2-one.

17. 3-N-(N',N-diethylaminoethyl) aminomethylene- 17u-ethinyl-androstan-17,6-ol-2-one.

References Cited in the file of this patent De Stevens et al.: J. Org. Chem., vol. 26 (May 1961), pp. 16144617.

Ketcheson et 211.: Canadian Jour. of Chemistry, vol. 38 (1960), pp. 972-979.

Disclaimer 3,128,269.Albet Bowen? and J 07m E dwa'r'ds, Mexico City, Mexico, and J 07m Zdem'c, Palo Alto, Calif. 3-AMINOMETHYLENE ANDRO- STANES. Patent dated Apr. 7 1964. Disclaimer filed J an. 24, 1966, by the inventors; the assignee, Syntax Corporation, assenting. Hereby enter this disclaimer to claims 1 and 6 of said patent.

[Oflicia-Z Gazette May 24, 1966.] 

1. A COMPOUND OF THE FOLLOWING FORMULA: 